Integrative Genomics Analysis Implicates Decreased FGD6 Expression Underlying Risk of Intracranial Aneurysm Rupture

INTRODUCTION: The genetic determinants of intracranial aneurysm rupture (rIA) are largely unknown. To identify and characterize genetic risk factors for rIA, we perform a genome-wide association study (GWAS) containing 84,353 individuals (7,843 rIA cases and 76,510 controls). We then use functional genomics approaches to delineate the mechanistic consequences of rIA risk loci. METHODS: We perform a meta-analysis across 24 published GWAS of rIA. Logistic regression was used to identify rIA-associated single nucleotide polymorphisms (SNPs). Gene-burden, expression quantitative trait loci (eQTL) mapping, and analysis of publicly-available single-cell RNA sequencing (scRNA-seq) data from normal human brain endothelial and perivascular cells was used to delineate cell-lineage expression of rIA-associated genes. RESULTS: We identify 5 independent genetic loci reaching genome-wide significance (p < 5.0 x 10-8) for rIA: rs73392700 (CDKN2B, OR = 1.12), rs6841581 (EDNRA, OR = 0.77), rs11661542 (RBBP8, OR=0.84), rs62516550 (RP1, OR = 1.20), and rs12310399 (FGD6, OR = 1.16). FGD6, to our knowledge, has not been implicated in prior GWAS of (r)IA. We then quantified gene-level mutation-burden across ∼20,000 genes, and only FGD6 (containing 21 rIA-associated SNPs) reached transcriptome-wide significance. Functional eQTL mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. scRNA-seq identified high expression of FGD6 in 1 of 3 arterial lineages, but absent in perivascular cells, identifying the likely cell-lineage underlying FGD6-mediated rIA risk. CONCLUSIONS: We perform the largest genetic study of rIA to date. We identify and characterize a previously unknown risk loci for rIA containing FGD6. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA enabling early treatment and improved patient outcomes.

IntroductionIntraprocedural intracranial aneurysm rupture is one of the most critical possible complications during endovascular treatment.Aim of StudyThe aim of this study was to evaluate the risk of intracranial aneurysm rupture...

The relationship between staying up late and risk of intracranial aneurysm rupture: A single-center study

Chronic inflammation is postulated as an important phenomenon in intracranial aneurysm wall pathophysiology. This study was conducted to determine if aspirin use impacts the occurrence of intracranial aneurysm rupture. Subjects enrolled in the International Study of Unruptured Intracranial Aneurysms (ISUIA) were selected from the prospective untreated cohort (n=1691) in a nested case-control study. Cases were subjects who subsequently had a proven aneurysmal subarachnoid hemorrhage during a 5-year follow-up period. Four control subjects were matched to each case by site and size of aneurysm (58 cases, 213 control subjects). Frequency of aspirin use was determined at baseline interview. Aspirin frequency groups were analyzed for risk of aneurysmal hemorrhage. Bivariable and multivariable analyses were performed using conditional logistic regression. A trend of a protective effect for risk of unruptured intracranial aneurysm rupture was observed. Patients who used aspirin 3× weekly to daily had an OR for hemorrhage of 0.40 (95% CI, 0.18-0.87); reference group, no use of aspirin), patients in the "< once a month" group had an OR of 0.80 (95% CI, 0.31-2.05), and patients in the "> once a month to 2×/week" group had an OR of 0.87 (95% CI, 0.27-2.81; P=0.025). In multivariable risk factor analyses, patients who used aspirin 3 times weekly to daily had a significantly lower odds of hemorrhage (adjusted OR, 0.27; 95% CI, 0.11-0.67; P=0.03) compared with those who never take aspirin. Frequent aspirin use may confer a protective effect for risk of intracranial aneurysm rupture. Future investigation in animal models and clinical studies is needed.

This study analyzed the rupture risk of intracranial aneurysms (IAs) according to aneurysm characteristics by comparing the differences between two aneurysms in different locations within the same patient. We utilized this self-controlled model to exclude potential interference from all demographic factors to study the risk factors related to IA rupture. A total of 103 patients were diagnosed with IAs between January 2011 and April 2015 and were enrolled in this study. All enrolled patients had two IAs. One IA (the case) was ruptured, and the other (the control) was unruptured. Aneurysm characteristics, including the presence of a daughter sac, the aneurysm neck, the parent artery diameter, the maximum aneurysm height, the maximum aneurysm width, the location, the aspect ratio (AR, maximum perpendicular height/average neck diameter), the size ratio (SR, maximum aneurysm height/average parent diameter) and the width/height ratio (WH ratio, maximum aneurysm width/maximum aneurysm height), were collected and analyzed to evaluate the rupture risks of the two IAs within each patient and to identify the independent risk factors associated with IA rupture. Multivariate, conditional, backward, stepwise logistic regression analysis was performed to identify the independent risk factors associated with IA rupture. The multivariate analysis identified the presence of a daughter sac (odds ratio [OR], 13.80; 95% confidence interval [CI], 1.65–115.87), a maximum aneurysm height ≥7 mm (OR, 4.80; 95% CI, 1.21–18.98), location on the posterior communicating artery (PCOM) or anterior communicating artery (ACOM; OR, 3.09; 95% CI, 1.34–7.11) and SR (OR, 2.13; 95% CI, 1.16–3.91) as factors that were significantly associated with IA rupture. The presence of a daughter sac, the maximum aneurysm height, PCOM or ACOM locations and SR (>1.5±0.7) of unruptured IAs were significantly associated with IA rupture.

BackgroundAneurysm location is a key element in predicting the rupture risk of an intracranial aneurysm. A common impression suggests that pure ophthalmic aneurysms are under-represented in ruptured intracranial aneurysms (RIAs)....

BackgroundPrevious results on the association between HDL (high-density lipoprotein cholesterol) levels and intracranial aneurysm (IA) rupture were controversial. We aimed to investigate the association between HDL levels and the risk of IA rupture.MethodsMedical records of patients with solitary IA diagnosed at West China Hospital of Sichuan University were reviewed and analyzed between December 2008 and March 2023. Univariable and multivariable logistic regression analyses were performed to determine the effects of HDL levels on IA rupture risk. A three-piece-wise logistic regression model with smoothing was used to analyze different association thresholds between HDL and the risk of IA rupture after adjusting for confounding factors.ResultsUnivariable and multivariable logistic regression analysis showed the independent association between HDL and IA rupture. After being adjusted for confounders, different U-shaped relationships were found between HDL levels and the risk of IA in males, females, and all patients. Compared to HDL in the range of 0.9 ~ 1.3 mmol/L, patients had 79% [OR (95%CI):1.79(1.16 ~ 2.78), p = 0.009] increase of rupture when lower than 0.9 mmol/L, 60% [OR (95%CI):1.6(1.19 ~ 2.17), p = 0.002] increase when higher than 1.3 mmol/L before or after adjusted confounders. We found gender differences in the HDL range of IA rupture; the lowest range of HDL was 1.1 ~ 1.4 mmol/L in females and 0.8 ~ 1.1 mmol/L in males.ConclusionsThere was a U-shaped relationship between HDL levels and the risk of IA rupture. People with HDL levels between 0.9 and 1.3 mmol/L are least likely to experience IA rupture in the Chinese population.

Although hypertension is a known risk factor for intracranial aneurysm rupture, the benefit of the management of blood pressure in reducing the rupture risk of intracranial aneurysms remains largely unknown, especially for regular blood pressure monitoring. We conducted a retrospective analysis of a prospectively maintained database of 3965 patients with saccular intracranial aneurysms from 20 medical centers in China. The patients were divided into the non-hypertensive group and hypertensive group. Propensity score matching was applied to identify a cohort of patients with similar baseline characteristics. Univariable and multivariable logistic regression analyses were performed to determine the association between intracranial aneurysm rupture and the management of blood pressure. After matching, hypertension was significantly associated with an increased rupture risk of intracranial aneurysms (OR = 2.559, 95%CI = 2.161-3.030, P = 0.000). For the management of blood pressure, controlled hypertension (OR = 1.803, 95%CI = 1.409-2.307, P = 0.000), uncontrolled hypertension (OR = 2.178, 95%CI = 1.756-2.700, P = 0.000), and hypertension without regular blood pressure monitoring (OR = 5.000, 95%CI = 3.823-6.540, P = 0.000) were all significantly associated with a higher rupture risk compared with the absence of hypertension. Moreover, hypertension without regular blood pressure monitoring was associated with a higher rupture risk compared with either controlled hypertension (OR = 3.807, 95%CI = 2.687-5.395, P = 0.000) or hypertension with regular blood pressure monitoring (including controlled and uncontrolled hypertension) (OR = 2.893, 95%CI = 2.319-3.609, P = 0.000). The absence of regular blood pressure monitoring was significantly associated with an increased risk of intracranial aneurysm rupture, emphasizing the importance of implementation of regular blood pressure monitoring in hypertensive patients with intracranial aneurysms.

Thermodynamics and structural stability of tissues for bio-imaging analysis – The case of intracranial aneurysm rupture risk assessment

The clinical ability of radiomics to predict intracranial aneurysm rupture risk remains unexplored. This study aims to investigate the potential uses of radiomics and explore whether deep learning (DL) algorithms outperform traditional statistical methods in predicting aneurysm rupture risk. This retrospective study included 1740 patients with 1809 intracranial aneurysms confirmed by digital subtraction angiography at two hospitals in China from January 2014 to December 2018. We randomly divided the dataset (hospital 1) into training (80%) and internal validation (20%). External validation was performed using independent data collected from hospital 2. The prediction models were developed based on clinical, aneurysm morphological, and radiomics parameters by logistic regression (LR). Additionally, the DL model for predicting aneurysm rupture risk using integration parameters was developed and compared with other models. The AUCs of LR models A (clinical), B (morphological), and C (radiomics) were 0.678, 0.708, and 0.738, respectively (all p < 0.05). The AUCs of the combined feature models D (clinical and morphological), E (clinical and radiomics), and F (clinical, morphological, and radiomics) were 0.771, 0.839, and 0.849, respectively. The DL model (AUC = 0.929) outperformed the machine learning (ML) (AUC = 0.878) and the LR models (AUC = 0.849). Also, the DL model has shown good performance in the external validation datasets (AUC: 0.876 vs 0.842 vs 0.823, respectively). Radiomics signatures play an important role in predicting aneurysm rupture risk. DL methods outperformed conventional statistical methods in prediction models for the rupture risk of unruptured intracranial aneurysms, integrating clinical, aneurysm morphological, and radiomics parameters. • Radiomics parameters are associated with the rupture risk of intracranial aneurysms. • The prediction model based on integrating parameters in the deep learning model was significantly better than a conventional model. • The radiomics signature proposed in this study could guide clinicians in selecting appropriate patients for preventive treatment.

Background: The occurrence of intracranial aneurysms is higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the healthy population. However, research concerning the factors related to the risk of intracranial aneurysm rupture in patients with ADPKD is still insufficient. Objectives: The aim of the study was to investigate the prevalence of intracranial aneurysms and aneurysmal subarachnoid hemorrhage (SAH) and to analyze the systemic factors associated with high-risk aneurysms in patients with ADPKD. Methods: We screened patients who underwent cerebral angiography between January 2007 and May 2017 in the ADPKD registry. Patients were examined for the presence of intracranial aneurysms and subsequently reclassified into 3 groups based on the risk of aneurysmal rupture: the aneurysm-negative (group 1), low-risk aneurysm (group 2), or high-risk aneurysm (group 3). Various systemic factors were compared, and independent factors associated with high-risk aneurysms were analyzed. Results: Among the 926 patients, 148 (16.0%) had intracranial aneurysms and 11 (1.2%) had previous aneurysmal SAH. Patients with intracranial aneurysms were further classified into group 2 (low-risk aneurysms, 15.5%) or group 3 (high-risk aneurysms, 84.5%). Age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01–1.05, p = 0.004), female sex (OR 3.13, 95% CI 1.94–5.0 6, p < 0.001), dolichoectasia (OR 8.57, 95% CI 1.53–48.17, p = 0.015), and mitral inflow deceleration time (DT) (OR 1.01, 95% CI 1.00–1.01, p = 0.046) were independently associated with high-risk aneurysms, whereas hypercholesterolemia (OR 0.46, 95% CI 0.29–0.72, p = 0.001) was negatively associated. Conclusion: In the present study among patients with ADPKD, the prevalence of intracranial aneurysms and aneurysmal SAH was 16 and 1.2%, respectively. Age, female sex, dolichoectasia, and mitral inflow DT were positively associated with high-risk aneurysms, whereas hypercholesterolemia was negatively associated. A subsequent large-scaled longitudinal study is needed to define the plausibility of the clinical parameters.

Relationship between cerebrovascular atherosclerotic stenosis and rupture risk of unruptured intracranial aneurysm: A single-center retrospective study

Since completion of the draft sequence of the human genome in 2000, the landscape of biomedical research has undergone a rapid transformation. Growing knowledge of genome structure and variation has spawned the development of technologies that allow researchers to study thousands of genes, transcripts, and proteins simultaneously. This has expanded biomedical science beyond reductionist approaches that test the function of individual genes to less biased approaches that study the behavior of many or all genes in homeostasis and disease. Such studies have been grouped under the broad label of functional genomics, which can be defined as the branch of biology that seeks to uncover the properties and function of the entirety of the genes and gene products of an organism.1 Functional genomics is fueling an explosion of new insights in biology and medicine, and many of these insights were completely unanticipated. Because these advances have begun to influence clinical practice,2,3 physicians will be expected to understand the potential uses and limitations of functional genomics in clinical settings. The purpose of this review is to provide a conceptual overview of functional genomics applied to the practice of cardiovascular medicine. We begin with a review of commonly used terms and approaches and then describe examples of their use for screening, diagnosis, and treatment selection in clinical cardiology. We also highlight emerging trends and speculate about where the field is headed in the near term. Although some predictions will be overly optimistic and some major advances unanticipated, we hope this review will help prepare cardiologists for their role in the application of genome science to the diagnosis and treatment of disease. This review is part of a series that introduces several related areas of cardiovascular genetics and genomics.4 We refer to these other contributions to guide further reading …

Introduction: To study the association between specific circular RNAs and rupture of intracranial aneurysm. To explore its clinical diagnostic significance and synergistic effects with individual environmental influencing factors.Methods: Three hundred and forty seven cases and controls were included in this study. Multivariate analysis was used to explore the main individual environmental factors. Intracranial aneurysm rupture related circular RNAs screened based on sequencing was verified in peripheral blood by PCR. ROC curve, logistic regression model and fork analysis were used to study the association, diagnostic values, and synergistic effects of circular RNA with intracranial aneurysms and individual environmental factors.Results: Smoking, hair dyeing, sitting time ≥6 h/day, single animal oil intake and hypertension are the main risk factors for intracranial aneurysm rupture; People with higher education, sleeping time ≥7 h/day, tea drinking, diabetes, higher levels of (hemoglobin, low density lipoprotein, serum calcium, and apolipoprotein-A1) have a low risk of intracranial aneurysm rupture. Hsa_circ_0008433 and hsa_circ_0001946 are closely related to intracranial aneurysm rupture and have certain clinical diagnostic significance (AUC = 0.726; 95% CI: 0.668~0.784). Hsa_circ_0008433 (OR = 0.497, 95% CI: 0.338~0.731), hsa_circ_0001946 (OR = 0.682, 95% CI: 0.509~0.914) were independent epigenetic factors affecting intracranial aneurysm rupture, and have a multiplicative interaction with age (OR = 3.052, 95% CI: 1.006~9.258).Conclusions: Low expressions of hsa_circ_0008433 and hsa_circ_0001946 are risk factors for intracranial aneurysms rupture and have good clinical diagnostic value. There was a multiplicative interaction between epigenetic score and age. The older and the higher the epigenetic score was, the more likely to have intracranial aneurysm rupture.

ObjectiveThis study compared 2 representative cases with ruptured aneurysms to explore the role of hemodynamic and morphological parameters in evaluating the rupture risk of intracranial aneurysms (IAs).MethodsCTA and 3-dimensional rotational angiography (3DRA) of 3 IAs in 2 patients were retrospectively analyzed in this study. Hemodynamics and morphological parameters were compared between a ruptured IA and an unruptured IA in case1, and between before and after aneurysm rupture in case 2.ResultsIn case 1, the ruptured aneurysm had larger morphological parameters including size ratio (SR), aspect ratio (AR), aneurysm vessel angle (θF), Aneurysm inclination angle (θA), Undulation index (UI), Ellipticity index (EI), and Non-sphericity Index (NSI) than the unruptured aneurysm. And oscillatory shear index (OSI) is also larger. Higher rupture resemblance score (RRS) was shown in the ruptured aneurysm. In case 2, the aneurysm had one daughter sac after 2 years. Partial morphological and hemodynamic parameters including SR, AR, θF, θA, UI, EI, NSI, OSI, and relative residence time (RRT) increased, and normalized wall shear stress (NWSS) was significantly reduced. RRS increased during this period.ConclusionSR and OSI may have predictive values for the risk of intracranial aneurysm rupture. It is possible that WSS Changes before and after IA rupture, yet the influence of high or low WSS on growth and rupture of IA remains unclear. RRS is promising to be used in the clinical assessment of the rupture risk of IAs and to guide the formulation of treatment plans.